Phenylcyclopropylamine -10-(omega-aminoalkyl)-phenothiazine ataractic composition



United States Patent 3,011,945 PHENYLCYCLOPROPYLAMINE 10 (w AMINO- ALKYL) -PHENOTHIAZINE ATARACTIC COM- POSITION Charles L. Bolling, Basement, and Carl R. Stevenson, Springfield, Pa., assignors to Smith, Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania N Drawing. Filed Mar. 7, 1960, Ser. No. 12,917 12 Claims. (Cl. 167-65) This invention relates to novel at-aractic compositions and the method of treating emotionally disturbed human beings with these compositions. More specifically this invention relates to ataractic compositions comprising 2-phenylcyclopropylamine derivatives combined with (w --aminoalkyl) phenothiazine derivatives and the method of treating disturbed human beings using such compositions.

Prior to the present invention the major disadvantage of drug treatment for depressed patients was the delayed onset of improvement following the initiation of therapy. Clinical improvement in those patients who responded favorably was not usually noted for several weeks. It is obvious that because of this very slow onset of action the physician loses patient cooperation which in turn leads to a loss of positive therapy. There is always the risk of suicide when treating depressed patients, and each day that depression persists the risk continues to grow; it is imperative to obtain a remission as quickly as possible. Still another disadvantage of this slow onset of action apparent when treating the mentally depressed by the prior art antidepressants is that the cost of treatment is much greater because medication is being taken for weeks, at times 60 days of treatment may be necessary before improvement is noticeable. Another great disadvantage is that if side effects were to develop during therapy it would take a longer period of time to alleviate them.

The novel ataractic or antidepressant compositions of this invention which couple 2-phenylcyclopropylamine amine oxidase inhibitors and l0-(w-aminoalkyl)-phenothiazine tranquilizing agents usually combined with a nontoxic pharmaceutical carrier unexpectedly produce a very rapid onset of action when utilized for the treatment of mentally depressed patients. A favorable response is noted as early as the first day of treatment. Whereas prior ataractic or antidepressant compositions have taken weeks before a general therapeutic response is evidenced, the novel compositions of this invention takes only a maximum of several days. This rapid onset or action overcomes all the disadvantages noted above.

The novel ataractic compositions of this invention are also advantageous in that they afford the beneficial efiects of the 2 -phenylcyclopropylamine analogues and the 10-(w-aminoalkyl)-phenothiazine derivatives in emotionally disturbed patients with a reduction of side eifects caused by the individual drug components of the compositions when such components are used alone.

Still another major advantage of the ataractic compositions of this invention is that they are useful in the treatment of a much broader spectrum of mentally disturbed patients than any ataractic compositions heretofore known.

More specifically, the compositions of this invention are in dosage unit form and comprise a phenylcyclopropylamine free base, preferably in the trans-configuration, or a nontoxic pharmaceutically acceptable acid addition salt thereof, the free base having the formula:

3,011,945 Patented Dec. 5, 1961 "ice Formula II in which X is hydrogen, chloro, trifluoromethyl, methyl, methoxy or methylthio.

A represents n-propylene or Z-methyl propylene.

Z is a basic N-connected terminal group, for example, dimethylamino, methylpiperazinyl, hydroxyethylpipera- Zinyl, hydroxyethoxyethylpiperazinyl, acetoxyethylpiperazinyl or methylpiperidyl.

Preferably the compositions of this invention in dosage unit form comprise a nontoxic pharmaceutical carrier with a 2-phenylcyclopropylamine derivative combined with Z-trifluoromethyllO- 3-( 1methyl-4-piperazinyl propyl] phenothiazine (trifiuoperazine), Y 2-chloro-10-(3-dimethylaminopropyl) -phenothiaz.ine

(chlorpromazine) 2-chlor0-1 0- 3- l-methy1-4-piperazinyl) propyl] -phenothiaz'ine (prochlorperazine), 10- 1-rnethyl-3-piperidyl) methyl] -phenothiazine (mepazine), 10- S-dimethylamino-Z-methylpropyl) -2-methylthiophenothiazine (methiomeprazine) 10-( 3-dimethylaminopropyl) -phenothiazine (promazine) 2-chloro-l0-[3-( N'-2-hydroxyethylpiperazinyl)propyl]- phenothiazine (perphenazine) 2-chloro-l 0- 3 (N-2-acetoxyethylpip erazinyl) propyl] phenothiazine (thiopropazate),

Z-trifluoromethyl-l 0- [3 '-N'-Z-hydroxyethylpiperazinyl propyl1phenothiazine (fluphenazine) 2-trifluoromethyll 0- 3 -dimethylaminopropyl -phenothiazine(trifiupromazine), or 10-(2-dimethyl-l-propyl)-phenothi'azine (promethazine) Most advantageously the compositions of this invention in dosage unit form are comprised of trans-2-phenylcyclopropylamine sulfate and 2 trifluoromethyl 1013- (1-methyl-4-piperazinyl)propyl] phenothiazine dihydrochloride. Either can alternatively be used in the form of another nontoxic, pharmaceutically acceptable acid addition salt.

Exemplary of other salts that can be used are those derived from nitric, phosphoric, citric, acetic, lactic, mandelic, salicylic, tartaric, ethanedisulfonic, sulfamic, acetylsalicylic, suecinic, fumaric, maleic, hydrobromic, benzoic and like nontoxic acids. The salts are best prepared by reacting the free base with a stoichiometric amount of the desired organic or inorganic acid in a suitable solvent such as ethyl acetate-ether solution, ethanol, acetone, water or various combinations 'of solvents.

Advantageously the 2-phenylcyclopropylamine and the phenothiazine derivatives represented by the above formulae or nontoxic acid addition salts thereof will be administered in a preparation comprising a pharmaceutical carrier and will be present in amounts sufiicient to produce ataraxia in emotionally disturbed human beings. Preferably the preparation will contain the Z-phenylcyclopropylamine derivative in an amount of from about 1 mg. to about 150 mg. and the phenothiazine derivative in an amount of from about 0.5 mg. to about 50 mg. per dosage unit. Advantageously the preparation will contain the 2- phenylcyclopropylamine in an amount of from about mg. to about 100 mg. and the phenothiazine derivative in an amount of from about 1.0 mg. to about mg. per dosage unit. Most advantageously the preparation will contain trans-Z-phenylcyclopropylamine sulfate in an amount of from about 10 mg. to about mg. and 2-trifluoromethyl-10-[3-(l-methyl 4 piperazinyl)propyl]- phenothiazine dihydrochloride in an amount of from about 1.0 mg. to about 10 mg.

The pharmaceutical carrier may be, for example, either a solid or a liquid. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Exemplary of liquid carriers are peanut oil, olive oil, sesame oil and water. Similarly the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a Wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm. If a liquid carrier is used, the preparation may be in the form of a solft gelatin capsule, placed in an ampule or in a liquid suspension.

Themethod in accordance with this invention comprises administering internally a composition comprising a 2- phenylcyclopropylamine derivative combined with a 10- (w-aminoalkyl)-phenothiazine derivative or nontoxic addition salts thereof, for example, any of the above compositions. The 2-phenylcyclopropylamine ingredient and the phenothiazine ingredient preferably will be per unit, in an amount of about 1 mg. to about 150 mg. of the 2- phenylcyclopropylamine and from about 0.5 mg. to about mg. of the phenothiazine derivative. Most advantageously the 2-phenylcycloproylamine ingredient will be present in an amount of about 10 mg. to about 100 mg. and the phenothiazine compound will be present in an amount of about 1.0 mg. to about 15 mg. per unit dose. The administration may be parenterally or orally, the latter being the preferable route of administration. Advantageously equal doses will be administered one to three times daily. Preferably the daily dose will be from about 1 mg. to about 450 mg. of the 2-phenylcyclopropylamine and from about 0.5 mg. to about 150 mg. of the phenothiazine compound and most advantageously from about 10mg. to about 300 mg. of the 2-phenylcyc1opropylamine and from about 1.0 mg. to about 45 mg. of the phenothiazine compound. Most advantageously the daily dose will be from about 10 mg. to about 75 mg. of trans- 2-phenylcyclopropylamine sulfate and from about 1.0

4 Example 1 Ingredients: Mg./ tab. Trans-2-phenylcyclopropylamine sulfate 10 Z-trifluoromethyl 10 [3-(l-methyl-4-piperazinyl) propyl] phenothiazine dihydrochloride 1 Calcium sulfate, dihydrate 150 Acacia 6 Alpha cellulose 9 Sugar crystals 5 Magnesium stearate 1 Starch 10 The trans-2-phenylcyclopropylamine, Z-trifluoromethyll0-[3-(1-methyl-4-piperazinyl)propyl1phenothiazine, calcium sulfate dihydrate and acacia are thoroughly mixed. The alpha cellulose is then added to the above ingredients and mixed well. The mixture is wet with water which was previously warmed to 50 F. The wet granulation is then placed on drying trays and the sugar crystals are sprinkled over the granulation. The granulation is then dried over night at F. The dried granulation is passed through a #12 mesh screen. The starch and magnesium stearate are added, the ingredients mixed and again screened through a #60 mesh screen. The granulation is then compressed into tablets.

One tablet is administered orally three times a day.

Example 2 Ingredients: Amounts, mg. Chlorpromazine hydrochloride 5 Trans 2 phenylcyclopropyldimethylamine sulfate 25 Magnesium stearate 2 Lactose The above ingredients are thoroughly mixed and filled into a #2 hard gelatin capsule.

One capsule is administered orally twice a day.

Example 3 Ingredients: Amounts, gm. Prochlorperazine ethanedisulfonate 0.75 TransQ-phenylcyclopropylamine hydrochloride 1.50 Sodium saccharin 0.10 Sodium biphosphate 0.75 Sodium tartrate l.00

Water for injection, q.s'. to 100.00 ml.

Dissolve the sodium biphosphate and sodium tartrate in 50% of the Water, add and dissolve the prochlorperazine ethanedisulfonate and trans-Z-phenylcyclopropylamine hydrochloride. Dissolve the sodium saccharin in 30% portion of the Water, add to the buffered drug solution, adjust to final volume with water for injection, filter through a bacetriological filter, fill into 2 ml. flint ampuls, seal ampuis and autoclave.

Distilled water, q.s. to 100.00 ml.

Dissolve the fiuphenazine hydrochloride, Z-phenylcyclopropylamine sulfate, soluble saccharin, sodium benzoate, citric acid and ascorbic acid in the distilled water add the sugar syrup, stir and filter. The oil of orange and oil of custard flavor are then added and the mixture thoroughly stirred.

One teaspoonful is administeredorally three times a day.

Example Ingredients: Amounts, mg. Perphenazine citrate l0 Z-phenylcyclopropylamine maleate 50 Magnesium stearate 2 Lactose 240 The ingredients are mixed and filled into a #Z-hard gelatin capsule.

One capsule is administered daily.

Example 6 Ingredients: Amounts, mg. Thiopropazate sulfate 2-phenylcyclopropylmethylarnine acetate 100 Lactose 150 The ingredients are mixed and filled into a #2 hard gelatin capsule.

Example 7 Ingredients: Amounts, mg. Triflupromazine hydrochloride 50 2-phenylcyclopropylamine maleate 150 Magnesium stearate 3 Lactose 200 The ingredients are mixed and filled into a #2 hard gelatin capsule.

Example 8 Ingredients: Amounts, mg. 2 trifluoromethyl -10-[3'-(N'-2-acetoxyethylpiperazinyl)propyl] -phenothiazine dihydrochloride 2-phenylcyclopropylamine tartrate 75 Peanut oil 200 The ingredients are mixed to a thick slurry and filled into a soft gelatin capsule.

The sucrose, calcium sulfate, 2-phenylcyclopropylamine sulfate and trifluoperazine dihydrochloride are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at 120 F. and passed through a mesh screen. These granules are then mixed with the starch, talc and stearic acid, passed through a #60 mesh screen and then compressed into tablets.

What is claimed is:

1. A pharmaceutical composition having ataractic activity in emotionally disturbed humans, in dosage unit form, comprising from about 1 mg. to about 150 mg. of a member selected from the group consisting of a free base and its nontoxic pharmaceutically acceptable acid addition salts, the free base having the formula:

OH: R:

in which R and R are members selected from the group consisting of hydrogen and methyl, and from about 0.5

mg. to about 50 mg. of a member selected from the group consisting of a free base and its nontoxic salts, the free base having the formula:

in which X is a member selected from the group consisting of hydrogen, chloro, trifluoromethyl, methyl, methoxy and methylthio, A is a member selected from the group consisting of propylene and 2-methyl-propylene and Z is a member selected from the group consisting of N-dimethylamino, N-(4-methylpiperazinyl) N-(4-hydroxyethylpiperazinyl) N-(4 hydroxyethoxyethylpiperazinyl) and N-(4-acetoxyethylpiperazinyl) 2. A pharmaceutical composition in accordance with claim 1 characterized in that said composition is combined with a pharmaceutical carrier.

3. A pharmaceutical composition having anti-depressant activity in emotionally disturbed human beings, in dosage unit form, comprising from about 1 mg. to about mg. of a compound having the fundamental formula:

and from about 0.5 mg. to about 50 mg. of a compound having the fundamental formula:

4. A pharmaceutical composition having ataractic activity in emotionally disturbed human beings, in dosage unit form, comprising from about 1 mg. to about 150 mg. of trans-2-phenylcyclopropylamine sulfate and from about 0.5 mg. to about 50 mg. of Z-trifiuoromethyl-IO- [3-( 1-methyl-4-piperazinyl) propyl] -phenothiazine.

5. A pharmaceutical composition in accordance with claim 4 characterized in that said composition is combined with a pharmaceutical carrier.

6. A method of treating emotionally disturbed human beings which comprises administering in an amount sufficient to produce ataraxia compounds of the class consisting of a free base and its nontoxic acid addition salts, the free base having the formula:

CH7 R1 in which R and R are members selected from the group consisting of hydrogen and methyl, and a member selected from the group consisting of a free base and its nontoxic acid addition salts, the free base having the and N-(4-acetoxyethylpiperaiinyl) said method producing a rapid onset of action.

and from about 0.5 mg. to about 150 mg. of a compound having the fundamental formula:

CHfiCHrCHrN N-CHJ said method producing a rapid onset of action.

9. The method of claim 8 in which the administration is orally to emotionally disturbed human beings.

10. A method of treatingemotionally disturbed human beings which comprises internally administering a daily dosage regimen of about 1 mg. to about 450 mg. of trans-Z- henylcyclopropylamine sulfate and from about 0.5 mg. to about 150 mg. of 2-trifluoromethyl-10 [3-(1- methyl 4 piperazinyl)propyl] phenothiazine dihydrochloride.

11. A method of treating emotionally disturbed human beings in accordance with claim 10 characterized in that the trans-2-phenylcyclopropylamine sulfate and the 2- trifluoromethyl 10 [3 (1 methyl 4 piperazinyl) propyl]-phenothiazine dihydrochloride are combined with a pharmaceutical carrier.

12. The method of claim 11 in which the administration is orally to emotionally disturbed human beings.

References Cited in the file of this patent Burger et al.: LACS. 70, pp. 2198-2199, 1948. American J. of Psychiatry, 115, 6, p. XIV, 1958. Reinhardt et al.: Am. J. of Psychiatry, 116, 1, 68, 1959. 

1. A PHARMACEUTICAL COMPOSITION HAVING ATARACTIC ACTIVITY IN EMOTIONALLY DISTURBED HUMANS, IN DOSAGE UNIT FORM, COMPRISING FROM ABOUT 1 MG. TO ABOUT 150 MG. OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF A FREE BASE AND ITS NONTOXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, THE FREE BASE HAVING THE FORMULA: 